Apolipoprotein E inhibits cerebrovascular pericyte mobility through a RhoA-mediated pathway [Cell Biology]

April 22nd, 2015 by Casey, C. S., Atagi, Y., Yamazaki, Y., Shinohara, M., Tachibana, M., Fu, Y., Bu, G., Kanekiyo, T.

Pericytes play a critical role in the cerebrovasculature within the central nervous system (CNS). These small contractile cells produce large quantities of apolipoprotein E (apoE) whose isoforms influence cerebrovascular functions and determine the genetic risk for Alzheimer's disease (AD). Despite extensive studies on astrocyte-secreted apoE, which supports synapses by transporting cholesterol to neurons, the biochemical properties and function of apoE secreted by pericytes are not clear. Since pericytes mediate important functions in the CNS including the initiation of glial scar formation, angiogenesis, and maintenance of the blood-brain barrier, we investigated the potential role of apoE in pericyte mobility. We found that knockdown of apoE expression significantly accelerates pericyte migration, an effect that can be rescued by exogenous apoE3, but not apoE4, a risk factor for AD. ApoE-regulated migration of pericytes also requires the function of the low-density lipoprotein receptor-related protein 1 (LRP1), a major apoE receptor in the brain that is abundantly expressed in pericytes. As apoE-knockdown also leads to enhanced cell adhesion, we investigated the role of apoE in the regulation of the actin cytoskeleton. Interestingly, we found that the levels of active RhoA are significantly increased in apoE-knockdown pericytes and that RhoA inhibitors blocked pericyte migration. Taken together, our results suggest that apoE has an intrinsic role in pericyte mobility, which is vital in maintaining cerebrovascular function. These findings provide novel insights into the role of apoE in the cerebrovascular system.